S-aminomethylpyrimtoines



. into'an Esterhalides:

United States Patent 2,698,326 I S-AMINOMETHYLPYRIMIDINES Hans Suter,Dorllingen, and Ernst Habicht, Schallllausen, Switzerland, assignors toCilag Limited, Schalfltausen, Switzerland, a Swiss company No Drawing.Application June 10, 1953, Serial No. 360,806

Claims priority, application Switzerland June 27, 1952 6 Claims. or.260-2564) in which R: is a hydrogen atom, an acyl, aroyl, alkyl or'aralkyl radical, R4 is an amino or hydroxy group, R5 is a cyano-,carbalkoxy-, carbamidoor aminomethyl group, Re is a hydrogen or an alkylradical and Z is an oxygen or a sul hur atom. a

It as been found that compounds of this formula have strongtuberculostatic effects. They are therefore intended for use asremedies, partly also as intermediate products for the production ofSchiifs bases with aromatic aldehydes.

The invention also provides a process for the production of the newpyrimidine derivatives by condensing a compound of the formula with acompound containing a radical of the formula in which X represents afunctional derivative of the carboxyl group containing and if necessarytransforming R: in the reaction product into an rill or aroyl group byacylation or aroylation, or

yl or aralkyl group by alkylation or aralkylation, or into a hydrogenatom by hydrolysis, and if necessary transf Compounds which give theradical of the Formula II include: Alkoxy methylene (Rs=H) malonic acidderivatives and alkoxy alkylene (R|=alkyl) malonic acid derivatives, forexample Dinitriles:

. (R==X=CN) Diesters: (Rs=X=OOO alkyl) Estermtnles:

(Rs or X===C0O alkyl; X or Rs=ON) swooo am; X=OO-ilal) orming Rs into acarbamido group by amidation, or into an amino methyl group byreduction.

Patented Dec. 28, 1954 Ester amidines:

hm.- Amidine amides:

(R, or X--C X or B -C ONHI) NHs Nitrile-amides:

(Rs or X= -CN; X or Rs=-CONH2) and other reactive derivatives of suchmalonic acids.

Compounds which contain the radical of the Formula II and carry basicgroups may also be used in the form of their acid salts; the amount ofalkali which is necessary for the neutralisation of the acid part may beadded to the reaction mixture at any time.

Alkylisothioureas and alkylisoureas may be used as such or in the formof their salts as compounds of the Formula I. it is also possible to usefree urea of thiourea. In general it has proved quite useful but notabsolutely necessary to work in the presence of a solvent or diluent.For this purpose alcohols are very useful, since they enable thenecessary amount of alkali to be added to the reaction mass in the formof alcoholates, i. e. under anhydrous conditions.

Where Rs is the cyano group, it can be reduced to the aminomethyl groupwith the usual reducing agents, e. g. with the aid of Raney nickel,preferably in alcohol saturated with ammonia. Furthermore, the followingreducing agents may also be used.

Lithium aluminium hydride in ether, chroma salts and other reducingagents known to the prior art Where Rs is a carbethoxy group it can beamidated preferably with ammonia in aqueous or alcoholic solution orwith liquid ammonia, with or without pressure, at high or lowtemperature.

The transformation of an alkyl or aralkyl radical R: by hydrolysis intoa hydrogen atom can easily be effected in acid solution. The splittingolf of an acyl or aroyl radical can take place in acid or alkalinesolution.

Where R: is a hydrogen atom, it can readily be transformed into an acylor aroyl radical by reacting a compound containing a radical of theformula III I alkali hydroxide, carbonate, bicarbonate, tertiary basessuch as pyridine or trialkylamines.

Alkylation or aralkylation is preferably eflected with the aid of areactive ester of an alkanol or aralkanol corresponding to R: in thepresence of basic condensation a ents, e. g. alkalis, alkali oxides,alkali hydroxides or car hates.

3 Preferred reactive esters are: Hydrohalide esters, and alkyl orarylsulphonic acid esters.

Example 1 o-Methylisourea methoxysulphonate, obtained from 18 gms. ofurea and 37.8 gms. of pure dimethyl sulphur, is reacted with 36.6 gms.of ethoxymethylene malodinitrile in 200 cc. of absolute methanol. Withshaking and cooling a cold solution of 10.5 gms. of sodium in 250 cc. ofabsolute methanol is added to this mixture, and the whole is put asidefor one day. The precipitated crystals are then recrystallised from hotwater. In this way 14-15 gms. of 2-methoxy-4-amino-S-cyano-pyrimidineare obtained, melting at 218-219 C. with decomposition. It exists incolourless glittering leaflets which are easily soluble in dilutedhydrochloric acid and sparingly soluble in alkalis.

Example 2 5 gms. of 2-methoxy-4-amino-S-cyano-pyrimidine, obtainedaccording to Example 1, and 4 gms. of lithium aluminium hydride aretreated with 400 cc. of absolute tetrahydro furane in a fine jet andwith intense stirring. The mixture is stirred at C., for two hours withcooling, then for another two hours at 4045 C., and then carefullytreated with water. The reaction mixture is evaporated to dryness,reacted with hydrochloric acid, boiled for half an hour and distilled.Then it is evaporated nearly to dryness, treated with 125 cc. of acetoneand cooled with ice and water. 1n this way 2 gms. of thedi-hydrochloride of 2-hydroxy-4-amino-5-aminomethyl pyrimidine areobtained decomposing at 264-267 C. Yield: 20%.

1 Example 3 22.2 gms. of S-benzyl isothiourea chloride, 23.8 gms. ofethoxy-methylene malonic acid diethyl ester and 250 cc. of ethanol arereacted with a solution of 5.1 gms. of sodium in 200 cc. of ethanol. Thereaction mixture becomes yellow and a crystalline mass separates. Afterone hours standing it is heated to boiling for one hour, then theethanol is distilled off and the residue is treated with 350 cc. ofwater, 30 cc. of 2 N hydrochloric acid and shaken. After 24 hours thecrystals are filtered off with suction and recrystallised fromdioxane/water. In this way 23.2 gms. of 2-benzylmercapto-4-hydroxy--carbethoxy pyrimidine are obtained melting at 172--173 C. Colourlessglittering leaflets which are hardly soluble in cold or hot water,ethanol, ether or acetone, but which in the heat are easily soluble inethyl acetate, benzene, chloroform and dioxane.

Example 4 2 benzylmercapto 4 hydroxy 5 carbethoxypyrimidine, obtainedaccording to Example 3, is reduced with lithium aluminium hydride intetrahydrofurane to the S-hydroxyrnethyl compound.

Example 5 In similar manner to that" described above, from 26 gms. ofethoxymethylene malonitrile, 44 gms. of S-benzylisothiourea chloride and5 gms. of sodium in a total of 600 cc. of absolute ethanol, 44 gms. of4-amino- 5-cyano-2-benzylmercapto pyrimidine are obtained, melting at171 C. Colourless crystals, recrystallisable from dioxane/water.

Example 6 Example 7 From 26 gms. of ethoxymethylene malodinitrile and 41gms. of S-ethylisothiourea bromide, with the aid of 5 gms. of sodium in400 cc. of ethanol, 21.5 gms. (56% of the theoretical) of2-ethyl-mercapto-4-amino-5-cyanopyrimidine melting at 147 are obtainedin a similar way. Colourless crystals, sparingly soluble in water,ethanol and benzene, easily soluble in ether, acetone, acetic ester,

chloroform and dioxane, recrystallisable from water, ethanol or benzene.

Example 8 10 gms. of 2-mercapto-4-amino-5-cyano pyrimidine, obtainedaccording to Example 8, are added to a solution of 1.5 gms. of sodium in50 cc. of ethanol. The sodium salt is separated by adding ether, thesalt is filtered off with suction and dried. Amount: 11.5 gms. The driedsodium salt is suspended in cc. of absolute dioxane and a solution of 10gms. of benzoyl chloride in 50 cc. of absolute dioxane is added withstirring. After 5 hours mechanical stirring at 20 C., the reactionmixture is heated to boiling and then cooled. After diluting with 500cc. of water, the reaction mass is adjusted to pHq with sodium hydroxideand the crystalline mass is filtered off with suction. Afterrecrystallisation from acetone/water or acetone/petroleum ether, 10-12gms. of 2-benzoylmercapto-4-amino-5-cyano pyrimidine are obtained, whichmelts at 176179 C. with decomposition. Colourless leaflets, sparinglysoluble in water, ether and benzene, fairly soluble in ethanol, acetoneand acetic ester. The compound is slowly saponified by boiling withdilute alkali.

Example 10 A solution of 30 gms. of 2-naphthyl methyl mercapto-4-amino-5-cyano pyrimidine in 225 cc. of tetrahydrofurane are addeddropby drop with icecooling and stirring to a solution of 15 gms. of lithiumaluminium hydride in cc. of absolute tetrahydrofurane within an hour.For 2% hours the mixture is mechanically stirred with ice-cooling, putaside for 24 hours and then carefully treated with a mixture ofdioxane/water. The whole is filtered, treated with 300 cc. of 2 N aceticacid and then concentrated in vacuo to about 200 cc. Afterwards it isagain diluted with 400 cc. of 2 N acetic acid, filtered with charcoaland the filtrate made alkaline with concentrated sodium hydroxide. Theprecipitated product is dissolved in 100 cc. of 2 N acetic acid,filtered and again made alkaline with sodium hydroxide. The precipitatedsubstance is dissolved in benzene and precipitated with petroleum ether.In this way Z-(naphthyl- (l')-methyl)-mercapto-4-amino-S-amino-methylpyrimitllizne obtained in colourless needles melting at 118-- Example 11From 13 gms. of 2,4-diamino-5-cyano-6-methyl pyrimidine and 11.5 gms. oflithium aluminium hydride in 370 cc. of tetrahydrofurane, 9.5 gms. ofthe hydrochloride of 2,4-diamino-6-methyl-5-aminomethyl pyrimidine areobtained by working as described in the foregoing examples. Whenrecrystallised from alcohol it melts at 255 C. with decomposition. Thefree base may be recrystallised from methanol and melts at C. withdecomposition.

The following may be obtained in the same manner as described in theforegoing examples:

(a) 2-hydroxy-4-amino-5-cyano pyrimidine, M. P.: 270

C. decomposition. M. P. picrate: 241-242 C.

(b) 2-benzylmercapto-4-amino-5-cyano-6-methyl pyrimidine, M. P.:193-196" C.

(c) 2 mercapto 4 amino 5 aminomethyl pyrimidine, M. P.: 220' C.decomposition.

(d) 2 benzylmercapto 4 amino 5 aminomethyl- 6-methyl-pyrimidine, M. P.:123123.5 C.

What we claim is:

l. The new chemical compound 2-methoxy-4-amino-5-amino-methyl-pyrimidine.

The new chemical compound 2-hydroxy-4-amino- 5-amino-methyl-pyrirnidine.

3. The new chemical compound 2-benzylmercapto-4-amino-5-aminomethyl-pyrimidine.

4. The new chemical compound 2-(naphthyl-(1')-methyl)mercapto-4-amino-S-aminomethyl-pyrimidine.

5. The new chemical compound 2-benzylmercapto-4-amino-5-aminomethyl-6-methyl-pyrimidine.

6. New chemical compounds selected from the group consisting of newpyrimidine derivatives of the general wherein R2 is a substituentselected from the group consisting of hydrogen, a low molecular alkylradical, a benzyl radical, and a naphthylmethyl radical, R4 is asubstituent selected from the'group consisting of an amino group and ahydroxyl group, R6 is a substituent selected from the group consistingof hydrogen and a low molecular alkyl radical, and Z is a memberselected from the group consisting of oxygen and sulfur, and salts ofsaid pyrimidine derivatives with nontoxic acids.

References Cited in the file of this patent Wheeler et al., Amer. Chem.Soc. Jour. 40, 237 (1908).

6. NEW CHEMICAL COMPOUNDS SELECTED FROM THE GROUP CONSISTING OF NEWPYRIMIDINE DERIVATIVES OF THE GENERAL FORMULA